Understanding the Role of Stereoelectronic Effects in Determining Collagen Stability. 2. A Quantum Mechanical/Molecular Mechanical Study of (Proline-Proline-Glycine)_n Polypeptides

Abstract

The importance of vicinal and long-range interresidue effects in determining the stability of the collagen triple helix has been investigated by quantum mechanical (QM) and molecular mechanical (MM) computations on suitable model polypeptides, taking into account solvent effects by the polarizable continuum model (PCM). At the QM level, the PII conformation corresponds to an energy minimum for pentapeptide analogues incorporating the sequence Gly-Pro-Pro-Gly, irrespective of the down or up puckering of the pyrrolidine ring. However, our computations indicate that the alternation of down and up prolines characterizing collagen and collagen-like peptides is not due to an intrinsic preference of the Pro-Pro-Gly sequence. This result is confirmed by MM computations of longer polypeptides. Next, MM computations on model triple helices show that a better packing is obtained for specific values of backbone dihedrals, which, in turn, favor the alternation of down and up prolines along each chain.

Hydroxylation-induced Stabilization of the Collagen Triple Helix

“…Vitagliano et al (27) predicted steric hindrance by modeling, if the proline in the Xaa position of -(Pro-Pro-Gly) n -triple helix is replaced by 4(S)Hyp. Quantum mechanical studies also come to this conclusion (25). However, this steric hindrance might be minimized by peptides with 4(S)Flp, which is smaller than 4(S)Hyp (17).…”

“…Raines and his colleagues (1,24) pointed out the importance of the inductive and stereoelectronic effects of the hydroxyl group of 4(R)Hyp. The importance of the pyrrolidine ring puckering of imino acids was shown with quantum and molecular mechanical analysis (25,26) and was supported by the "propensity-based" stabilization of proline in the Xaa position and 4(R)Hyp in the Yaa position and the destabilization of 4(R)Hyp in the Xaa position (27,28).…”

The Crystal Structure of a Collagen-like Polypeptide with 3(S)-Hydroxyproline Residues in the Xaa Position Forms a Standard 7/2 Collagen Triple Helix

“…In addition, quantum mechanical ab initio calculations have elucidated the specific roles of stereoelectronic effects, ring pucker, cis/trans stabilization, and / dihedral angles in Pro and 4(R)Hyp residues and the effect of these parameters in the stability of the collagen triple helix (17)(18)(19)(20). These studies * This work was supported by a grant from Shriners Hospital for Children and, in part, by a Burroughs Wellcome Career Development Award 992863 (to M. A. S.).…”

Computational Study of a Heterostructural Model of Type I Collagen and Implementation of an Amino Acid Potential Method Applicable to Large Proteins

“…Current computational efforts on collagen molecules focus mostly on their structures and mechanical properties under various assumptions and approximations [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39], and less on the electronic structure at the level of amino acids. Nevertheless, a classical description in biomolecular simulations has contributed tremendously in this area because they can be applied to much larger systems [36][37][38][39][40].…”